In Alzheimer's disease (AD), tau neuropathology correlates with severity of dementia. However, interventions for AD and related dementias are limited to treatment of symptoms that do not directly alter tau pathology or the resultant neurodegeneration. This underscores the need for tau-targeted disease-modifying therapeutics. Furthermore, the results from amyloid-targeted clinical trials in AD patients suggest that achieving cognitive preservation in AD may require tau-targeted therapy in conjunction with the removal of amyloid. Our work has demonstrated that MSUT2 controls neuronal susceptibility to tau toxicity in the mammalian brain. The mechanism of MSUT2 modulation of tauopathy appears to involve MSUT2 binding to poly(A) RNA and its modulation of RNA polyadenylation. The identification of small molecules that inhibit MSUT2 from binding to poly(A) RNA will provide a pharmacological means of intervening against tauopathy. We hypothesize that small- molecule antagonism of MSUT2/poly(A) RNA-binding after onset of pathological tau deposition will reverse the toxic consequences of pathological tau. The specific aims of this proposal will identify and develop potent and specific brain-penetrant MSUT2 inhibitors and use them to dissect the temporal and mechanistic relationship between MSUT2 activity and tauopathy. Completion of the project as proposed will also further demonstrate the importance of MSUT2 in Alzheimer's disease. This knowledge will set the stage for future translational studies by both generating MSUT2 specific tool compounds and validating a novel candidate therapeutic target for pharmacological intervention in tauopathy disorders.